Bronchodilator 5,6-dihydro-tetrazolo(1,5-c) quinazolines

ABSTRACT

Tetrazoloquinazoline compounds such as 5,6-dihydro-5-ethyl-8,9dimethoxy-5-methyl-tetrazolo(1,5-c)-quinazoline are prepared by the reaction of a 5-(2-aminophenyl)tetrazole with a ketone or aldehyde. The compounds are useful as bronchodilator agents.

United States Patent. 1191 Wagner 1 41 BRONCHODILATOR5,6-DIHYDRO-TETRAZOLO(1,5-C) QUINAZOLINES [75] Inventor: Eugene R.Wagner, Midland, Mich.

[73] Assignee: The Dow Chemical Company,

Midland, Mich.

22 Filed: Oct. 13,1972

211 Appl. No.: 297,467

[52] U.S. Cl 260/256.4 F, 424/251 [51] Int. Cl C07d 51/48 [58] Field ofSearch 260/256.4 F

[56] References Cited UNITED STATES PATENTS Mosby et al. 260/2564 1451Sept. 10, 1974 Primary Examiner-Raymond V. Rush Attorney, Agent, orFirm-Maynard R. Johnson 5 7] ABSTRACT 6 Claims, N0 Drawings 1 RONC ODILTO 5,6-DIHYDRO-TETRAZOLO(1,S-C) QUINAZOLINES BACKGROUND OF THE INVENTIONS-Substituted-tetrazolo (l,5-c)quinazolines and certain-hydroxy-5,6-dihydro-tetrazolo(l ,5-c) quinazo- GeterotsiklicheskikhSoedinenii, 2, 130 (1966) and 3: 944 (1967); and see Current Abstractsof Chemistry, 37 (340) 142673; 37 (337); 140057; and 39 (359) 1600 84-5.

The substituted 5-(2-aminophenyl)tetrazole employed as startingmaterials can be prepared by the reaction of the correspondinganthranilonitrile with sodium azide and ammonium chloride, by the methodof Finnegan et al., J. Am. Chem. Soc. 80, 3908 (1958) with the additionof lithium chloride, according to Ho]- land and Pereira, J. Med. Chem.10, 149 (1967). The anthranilonitriles can be prepared by known methods,McKee et al., .I. Am. Chem. Soc. 68, 1902 (1946), and 69, 940 (1947) andKeffler, J. Chem. Soc. 119, 1476 (1921 SUMMARY OF THE INVENTION Thisinvention is directed to 5,6-dihydrotetrazoloquinazoline compounds andis particularly directed to 5,6-dihydro-tetrazolo(l,5-c)quinazolinecompounds of the formula:

R: Rz- N R4 R1 /N\ l NN with an aldehyde or ketone corresponding toformula III lines have been prepared by Postovskii et al., Khimiya Inthe above formulae [1 and III, the moieties R R R and R have thesignificance set out above with respect to Formula I. The reactionproceeds when the reactants are contacted and mixed, preferably in thepresence of an inert organic solvent as a reaction medium. Suitableinert solvents include chloroform benzene, methanol, ethanol, propanoland isopropanol, and other inert organic liquids in which the reactantsare soluble, which liquids have a boiling point between about 0 and C.Ethanol is the preferred solvent of choice. The reaction proceeds attemperatures from about 0C. to about 130C. In many cases, the reactionproceeds at a desirably rapid rate at room temperature; in other casesit is desirable to heat the reaction mixture to the boiling temperatureunder reflux. The reaction is generally complete within about 5 minutesto about 4 hours, depending upon temperature, choice of solvent (ifused) and the particular reactants employed. The product can beseparated by conventional procedures, such as evaporation of reactionmedium and unreacted aldehyde or'ketone, or dilution and cooling of thereaction mixture to induce crystallization of the product. The productcan be purified by conventional procedures such as recrystallization andwashing.

The exact proportions of the reactants to be employed are not critical,some of the desired product being obtained when the reactants arecombined over a wide range of proportions (e.g., a ten fold molar excessof either reactant), the reaction consumes the reactants in equimolarproportions, and the presence of large excesses of the ketone oraldehyde starting material can make separation unnecessarily difficultdue to solubility of the product in the excess reactant. In a preferredprocedure, the reactants are employed in proportions from substantiallyequimolar amounts of each reactant to about 10 percent molar excess ofthe ketone or aldehyde reactant.

EXAMPLE 1 5-(2-Aminophenyl)tetrazole (2 grams; 0.012 mole) was dispersedin 30 milliliters of chloroform. 5 Milliliters (0.068 mole) of acetonewas added and the resulting solution was heated at the boilingtemperature until crystalsformed in the reaction mixture. The mixturewas filtered, and the product collected on the filter. The 5,6-dihydro-5 ,5dimethyl-tetrazolo( 1 ,5- c)quinazoline product was foundto melt at 202204C. Thestructure of the product was confirmed byinfrared spectroscopy and nuclear magnetic resonance analysis, and bymass spectroscopic determination of molecular weight [found m/e 201(M+); calculated 201.2].

5,6-Dihydro-5-cthyl-5-mcthyl-tetrazolo(1,5- c)quinazoline, melting atl44l45C., and 5,6- dihydro-S-methyl-tetrazo1o( 1,5-c)quinazoline-S-acetic acid, melting at 91-94C. are prepared insubstantially the same procedure.

' EXAMPLE 2 The following compounds are prepared as described aboveusing about 8 milliliters of ethanol per gram of substituted5-(2-aminophenyl)tetrazole reactant as a reaction medium and a S to 10percent molar excess of the aldehyde. The table identifies the compoundsand the reactants in reference to the R R R and R moieties set out abovewith reference to formulae 1. 11. 111.

TABLE I R, R2 R3 R4 M.P. Calc'd analysis Found analysis H H CH3 CH; .93;H, 5.58; N, 34.02. H H -CH2CH2CH2CH2 .90; H, 5.77; N, 30.81. H H H .34;11,4.14; N, n15. OCH; OCH; CH: CHECH. .24; H, 6.16; N, 25.12. OCH; OCHaH C s .00; H, 5.25; N, 28.58. -o oH,-o H CH3 .49; II, 4.02; N, 30.65. 11H H CH; .34; 11.6.10; N, 33.00.

mm; on", H /Clh 198-2 0 C, 56.71; II, 6.22; N, 25.44 0,513.07; H,6.06;N, 24.13

II 1! 1! cm H II It 00011 H 00H, 1-1 H H 00H. H CH; OCH; OCH; H H

EXAMPLE 3 20 10 milligrams per kilogram. In replicated operations In aprocedure similar to that described above 5,6-dihydro-S-propyl-tetrazolo( 1,5-c )quinazoline, melting at 11 ll 12C.was prepared by the room temperature reaction ofS-(Z-aminophenyl)tetrazole with excess butyraldehyde. No inert organicsolvent was employed, and the excess butyraldehyde was removed byevaporation. The product was crystallized from a mixture of ethanol andwater. Elemental analysis confirmed the assigned structure.

Bronchodilator activity of representative I tetrazoloquinazolinecompounds is examined in the KonzettRossler guinea pig preparationaccording to accepted procedures. See Konzett and Rossler; Arch. f. exp.Path. u. Pharmakol. 195: 7l74 (1940); and Rosenthale and Dervinis, Arch.int. Pharmacodyn 172: 91-94 (1968). In this procedure, an anesthetizedguinea pig is artificially respired with a fixed volume of air. Thisvolume of air is selected to exceed the lung capacity, and the excessoverflow volume is measured. Bronchoconstriction is produced byintravenous injection of a selected agonist (histamine, serotonin oracetylcholine) at minute intervals at a dosage selected to produce 50 to80 percent bronchoconstriction, as indicated by the resultant increasein overflow volume. Test compounds are evaluated by administering a testcompound two minutes before the next agonist dose following threeprevious agonist doses resulting in relatively uniform (i percent)bronchoconstriction. Bronchodilator activity, indicated by ability of atest compound to block the agonist response, is expressed in terms ofpercent block, calculated by dividing the agonist response(s) after thetest drug by the average of the three agonist response preceeding thetest compound, multiplying by 100 and subtracting this value from 100percent. Aminophylline, a known bronchodilator, is also employed as astandard for comparison. In such procedure percent block is determinedfor an intravenous dosage of 10 milligrams aminophylline per kilogram,then a test compound, then a repeat dos-- age of aminophylline. Theresults can be expressed as a percent of aminophylline, calculated byexpressing the percent blockade produced by the compound as a percentageof the average of the percent blockade produced by the doses ofaminophylline which precede and follow it.

Tetrazoloquinazoline test compounds are employed astestcornpoundsin thisprocedure at a dosage rate of with each compound,5,6-dihydro-tetrazolo(1,5- c)quinazloline, 5,6-dihydro-5-n-propyl-tetrazolo( 1,5-c) -c)quinazoline, 5,6-dihydro-5-ethyl-5-methyltetrazolo( 1 ,5-c )quinazoline,5,6-dihydro8,9- dimethoxy-S-ethyl-5-methyl-tetrazolo( 1,5-c)quinazoline,5,6-dihydro-8,9-dimethoxy-5-methyltetrazolo-(l,5-c)quinazoline, ethyl5,6-dihydro-5- methy1-tetrazolo-( 1,5-c )quinazoline-S-acetate and 5,6-dihydro-8,9-dimethyoxy-tetrazolo( l ,S-c)quinazoline are found to giveaverage percent block of histamine of 57, 28, 55, 45, 59, 20 and 43percent respectively, and to be about 82-, 44, 67, 95, 134, 30 andpercent, respectively, as active as aminophylline.

In similar operations, 5,6-dihydro-5-isopropyltetrazolo( l ,5-c)quinazoline is found to produce 50 and 60 percent blockade againstserotonin and acetylcholine, respectively, and to give results equal toor slightly greater than those obtained with aminophylline.

What is claimed is:

1. A 5,6-dihydro-tetrazolo(1,5-c)quinazoline compound corresponding tothe formula:

wherein R, and R each independently represent hydrogen or'lower alkoxy;or R, and R taken together represent methylenedioxy; R representshydrogen or methyl; R represents hydrogen, lower alkyl, earboxy,carboxymethyl, lower alkoxy carbonyl, or lower alkoxy carbonyl methyl,and R and R taken together represent butylene.

2. A compound of claim 1 wherein R, and R both represent methoxy.

3. A compound of claim 2 wherein R represents hydrogen.

4. A compound of claim 2 wherein R, represents methyl.

5. A compound of claim 1 wherein R, and R both represent methoxy, Rrepresents methyl and R, represents ethyl.

6. A compound of claim 1 wherein R,, R R and R all represent hydrogen.

gg g g UNITED STATES PATENT OFFICE- CERTIFICATE 0F CORRECTION Patent No.3.835.138 Dated September 10, 1974 Inventor(s) Eugene Wagner It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 1, line- 35, the formula should appear as follows:

H N R3 R2 6 R4 3 1 Column 4, line 29, correct spelling of "dimethoxy"; I

Column 4, line 45, the formula should appear as follows:

H R N R 2 R Signed and sealed this 10th day of December 1974.

(SEAL) Attest:

McCOY M. GIBSON JR. C. MARSHALL DANN Attesting Officer Commissioner ofPatents

2. A compound of claim 1 wherein R1 and R2 both represent methoxy.
 3. Acompound of claim 2 wherein R3 represents hydrogen.
 4. A compound ofclaim 2 wherein R4 represents methyl.
 5. A compound of claim 1 whereinR1 and R2 both represent methoxy, R3 represents methyl and R4 representsethyl.
 6. A compound of claim 1 wherein R1, R2, R3 and R4 all representhydrogen.